The Physiome Project and the Virtual Physiological Human · 2019. 12. 2. · Digestive system Skin...
Transcript of The Physiome Project and the Virtual Physiological Human · 2019. 12. 2. · Digestive system Skin...
Cardiac Physiome, 17-19th Oct 2013
The Physiome Project and the
Virtual Physiological Human
Peter Hunter Auckland University, New Zealand
History of Physiome Project
1999 Systems Biology Markup Language
2006 STEP: Strategy for European Physiome 2008 VPH Network of Excellence
2011 VPH Institute
2009 Drug Disease Model Resources (DDMoRe)
1997 IUPS Physiome Committee
1998 CellML, FieldML
2003 IMAG (NIH, NSF, FDA, NASA, DOE, DOD, ..)
2010 German Virtual Liver Network
Marco Viceconti
Denis Noble
Yoshi Kurachi
Andrew McCulloch
Dan Beard
Nic Smith
Stig Omholt
Adriano Henney
Jim Bassingthwaighte
Ilias Iakovidis
Physiome colleagues
VPH Institute
www.vph-institute.org
Virtual Liver Network
www.virtual-liver.de
www.vph-noe.eu/images/vph_vision_2011_23dec2010.pdf
To cope with the multi-physics, multi-scale, complexity of human biology
we must create reproducible models with modular approaches
based upon data and modeling standards
• Biophysically based models at every level – as much as possible (there’s always a black box!)
• Adoption of model and data standards – SBML, CellML, FieldML for models
• Automated assembly of multi-scale models – molecule to organ(ism)
• Automated model reduction – otherwise too expensive
A multi-scale bioengineering approach needs:
Verification, Benchmarks
Experimental measurements
Model standards: SBML, CellML, FieldML
Model repositories: Biomodels, PMR2
Data standards: DICOM, BioSignalML, ..
Minimum information standards: MIAME, MICEE, ..
Data repositories: PhysioNet, CAPdb, CVRG, ..
Standards for models, data & software
Validation, Limitations
(Journal review)
APIs, webservices
Software: JSim,OpenCOR, OpenCMISS, Continuity, Chaste, ..
Simulation standards: SED-ML Functional curation
APIs, webservices
Curation Annotation
Reference description
Metadata: Ontologies
Need modules!
Metadata: Ontologies GO, FMA, ..
Biophysical Journal
“To assure public access to computational models, authors are strongly encouraged to deposit their models in the CellML Model Repository models.cellml.org/cellml or Biomodels Database www.ebi.ac.uk/biomodels-main/”
Note on model publishing
Similarly for many other journals.
Cardiovascular system Respiratory system Musculo-skeletal system Digestive system Skin (integument) Urinary system Lymphoid system Female reproductive system Special sense organs Central nervous system Endocrine system Male reproductive system
Organ system Physiome Projects
Tissue
Osteon Nephron Acinus Liver lobule Lymph node Cardiac sheets
Organ
Heart Lungs Diaphragm Colon Eye Knee Liver
Environment
Organ system
Organism
Cell
Protein Gene Atom
Network
x 1million 20 generations
The challenge: organs to proteins
Key features
• Version controlled storage of models – They are encapsulated as Workspaces.
• Content management system (CMS) for presentation of models. – The set of presentation views is known as Exposures.
• Provides services to store, access and interact with models.
• Links with external web-services to provide semantic reasoning against model metadata across models.
Physiome model repository (PMR)
Tommy Yu
PMR for anatomical models - FieldML
Thor Besier Hugh Sorby
Musculo-skeletal system
Load generic models into the anatomical component under study:
Web-accessible database of generic models (+ tissue structure):
Generic models of the joints
Shim VB, Hunter PJ, Pivonka P, Fernandez JW. A multiscale framework based on the physiome markup languages for exploring the initiation of osteoarthritis at the bone-cartilage interface. IEEE Trans Biomed Eng. 58(12):3532-6, 2011
Population atlases
Alistair Young www.cardiacatlas.org Brett Cowan
PMR for cell models - CellML
(www.cellml.org)
Cuellar AA, Lloyd CM, Nielsen PF, Halstead MDB, Bullivant DP, Nickerson DP, Hunter PJ. An overview of CellML 1.1, a biological model description language.SIMULATION: Transactions of the Society for Modeling and Simulation, 79(12):740-747, 2003
Cell cycle (25 models)
Calcium dynamics (63 models) Cell migration (2 models)
Circadian rhythms (9 models) Endocrine system (29)
PKPD models (7 models)
Myofilament mechanics (15) Metabolism (35 models)
Electrophysiology (117 models) Excitation-contaction (15 models)
Gene regulation DNA repair (3) Synthetic biology (5 models)
Material constitutive
laws
Cardiac myocyte a-adrenergic
Muscarincic, ACh
PLCb
Ga Gbg PIP2
Gq
a1
DAG + IP3
Ca2+
CaN CaMK PKCa PKCd PKCb PKCe
b-adrenergic NE, Iso
PKA
ATP cAMP
Ga Ga Gbg
AC
Gi
b2
Gs
b1
MEF2C
GATA4
NFAT p
p p
TFs
t
V
Ca2+
EC-coupl.g & mechs
PLB Serca2
TnC
Ca2+
RyR2
TnI
MHC
p p
p
p
T
p
p
p
p p
ms seconds hours days Time scale
Nucleus
Membrane
Cytosol
DNA
Inputs
Outputs c-myc, c-fos, c-jun, ras, hsp-70
TFs
p
Eccentric hypertrophy Concentric hypertrophy
Physiological hypertrophy
CellML signalling modules for the cardiac myocyte
Ion channels, transporters
INa Na+
INa,b Na+
ICl Cl- ICa,L
Ca2+
ICa,T Ca2+
ICa,b Ca2+
IKr K+
IKs K+
IKto K+
IKp K+
IK1 K+
NCX
Ca2+
3Na+
3K+
2Na+ NKA
CHE OH-
NHE H+
NBC
HCO3-
Na+
AE
HCO3-
Cl- *
NO
sGC sGC
eNOS nNOS
Ca2+
NO
cGK I
p
cGK II
p
cGMP
pGC
ANP BNP
iNOS
NO
Peptide GFs
RAS
MAPK
ERK JNK p38K
TFs
RTK
p p p
p p p
p
Apoptosis
Cytokines
cytokine receptor
gp130
STAT
Jac IkB
NFkB
Inactive Class II HDACs
Ca2+
CaMK PKD
PKC
histone
Insulin, IGF, GH
TFs
mTOR
p
GSK3
p
PKB
PI3K
PIP3
RTK
p
Hypertrophic cardiac myopathy
FOXO
1. cAMP signalling 2. Calcium signalling - via cADP-ribose signalling NAADP signalling Voltage operated channels (VOCs) Receptor operated channels (ROCs) IP3-Ca2+ signalling (via PLC-PIP2) DAG-PKC signalling (via PLC-PIP2) PI4-5P2 signalling Inositol polyphosphate signalling PI3-Kinase signalling 3. NO-cGMP signalling 4. Redox signalling 5. MAP-Kinase signalling 6. NF-kB signalling 7. Phospholipase D (PLD) signalling 8. Sphingomyelin signalling 9. JAK-STAT signalling 10. Smad signalling 11. Wnt signalling 12. Hedgehog signalling 13. Notch signalling 14. ER stress signalling 15. AMP signalling
Signaling
• Glucose transporter (GLUT2) • Glucokinase (GK) • Glucose-6 phosphatase (G6Pase) • Glucose-6-phosphate isomerase (GPI) • Glucose-1-phosphate 1,6-phosphomutase (G16PI) • UTP: Glucose-1-phosphate uridylyltransferase (UGT) • Pyrophosphate phosphohydrolase (PPase) • Glycogen synthase (GS) • Glycogen phosphorylase (GP) • Nucleosid diphosphate kinase (NDK) • Adenylate kinase (AK) • Phosphofructo kinase 2 (PFK2) • Fructo-2,6-bisphosphatase (FBP2) • Phosphofructo kinase (PFK1) • Fructose-1,6-bisphosphatase (FBP1) • Aldolase (ALD) • Triosephosphate isomerase (TPI) • D-Glyceraldehyde-3-phosphate: NAD+
oxidoreductase (GAPDH) • Phosphoglycerate kinase (PGK) • 3-Phosphoglycerate mutase (PGM) • Enolase (EN) • Pyruvate kinase (PK) • Phosphoenolpyruvate carboxykinase (PEPCK) • Pyruvate carboxylase (PC) • Lactate dehydrogenase (LDH) • Lactate transporter (LACT) • Pyruvate transporter (PYRT) • PEP transporter (PEPT) • Pyruvate dehydrogenase (PDH) • Citrate synthase (CS) • Nucleosid diphosphate kinase (NDK) • Oxalacetate flux (OAAflx) • Acetyl-CoA flux (ACOAflx) • Citrate flux (CITflx)
6 month roadmap for OpenCOR
• CellML authoring. This will use the MathML renderer.
• Support for SED-ML (http://sed-ml.org) using Frank Bergmann's API: https://github.com/fbergmann/libSEDML
• Incorporate BioSignalML API
• CellML annotation using composites
• Drag & drop model building
Data standards
Model repositories
Software toolkits
Simulation datasets Ontologies
Biosignal repositories Browse
search query
METADATA Data collection
Simulation engines
www.BioSignalML.org
Semantic annotation of models
Ontologies: ChEBI - chemical IDs GO - cell component CellType - cells FMA - anatomy OPB - biophysics
Add new composite & Reclassify i.e. ‘calcium concentration in cytosol’ is indexed so x_URI can be found in search
x is calcium concentration in cytosol
Annotating CellML models
CellML Model
Metadata (semantics) Author, publications, etc Model annotations*
Maths (syntax) 𝑑𝑦
𝑑𝒕= 𝒇 𝒙, . . …
PMR Mercurial DVS Imports, provenance
OpenCOR • Authoring, curation • Annotation • Simulation
* www.cellml.org/specifications/metadata/mcdraft
SemGen Reasoning over OWL-KB OPB templates
Ricordo Reasoning over OWL-KB
(a property associated with an entity)
OWL knowledge base Has all reference ontologies. Chebi - calcium OPB - concentration GO (cell cpt) - cytosol FMA, … + units + composites
MIRIAM
Ricordo RDF Triple store Stored as RDF triple (3 URIs, one being the relation):
x_URI is_a_computational cpt_for composite_URI
SparQL queries
Adding Annotations: SemGen Max Neal
Drag & drop model building
David Nickerson
Acknowledgements: The CellML/FieldML team
Andrew Miller Randall Britten
Richard Christie
Alan Garny
David Nickerson
Tommy Yu
Mike Cooling
Hugh Sorby
Poul Nielsen
Alan Wu
NZ Health Research Council NZ Ministry of Science & Innovation NZ Maurice Wilkins Centre CoRE UK Wellcome Trust (Heart Physiome) FP7 (euHEART, NoE, VPH-Share) NIH (Cardiac Atlas Project - CAP)
Funding Acknowledgements
www.vph-institute.org